1,3-Diacyl derivatives of imidazolidine and hexahydropyrimidine

ABSTRACT

1,3-Diacyl imidazolidines and hexahydropyrimidines were prepared by the reaction of formaldehyde and an N,N&#39;&#39;-alkylene-bisamide in the presence of a strong acid catalyst, the substituent acyl groups being acetyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, palmitoyl, stearoyl, and oleoyl. These compounds exhibit antimycotic activity.

United States Patent [191 Mod et al.

[451 Apr. 1, 1975 1,3-DIACYL DERIVATIVES OF IMIDAZOLIDINE AND HEXAHYDROPYRIMIDINE 22 Filed: Mar. 4, 1974 21 Appl. No.: 448,428

Related U.S. Application Data [62] Division of Ser. No. 154,698, June 18, 1971,

abandoned.

.[52] U.S. Cl 260/251 R, 260/309.7, 424/251,

424/273 [51] Int. Cl. C07d 57/28, C07d 57/30 [58] Field of Search 260/251 R [56] References Cited OTHER PUBLICATIONS Chemical Abstracts, Vol. 74, (1971), page 470, par. 125,6185.

Primary E.\'aminerElbert L. Roberts Attorney, Agent, or FirmM. Howard Silverstein; Max D. Hensley [57] ABSTRACT 1,3-Diacyl imidazolidines and hexahydropyrimidines were prepared by the reaction of formaldehyde and an N,N'-alkylene-bisamide in the presence of a strong acid catalyst, the substituent acyl groups being acetyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, palmitoyl, stearoyl, and oleoyl. These compounds exhibit antimycotic activity.

11 Claims, N0 Drawings 1,3-DIACYL DERIVATIVES OF IMIDAZOLI- DINE AND HEXAHYDROPYRIMIDINE A non-exclusive, irrevocable, royalty-free license in the invention herein described, throughout the world for all purposes of the United States Government, with the power to grant sublicenses for such purposes, is hereby granted to the Government of the United States of America.

This is a division of application Ser. No. 154,698, filed June 18, 1971, now abandoned.

This invention relates to certain new nitrogen containing organic compounds and to a novel process for the preparation of these compounds. More particularly, this invention relates to N,N'-diacyl derivatives of imidazolidine P. N-C- CH2 l CH2 cn N I \C R and N,N'-diacyl derivatives of hexahydropyrimidine where R and R in formulas l and I] may be the same organic radical or different organic radicals containing from one to about twenty-one carbons, and may be saturated or unsaturated alkyl groups, or addition or substitution products thereof. The substituted imidazolidines and hexahydropyrimidines that are the subject of this invention are characterized by the fact that as growth inhibitors, they are effective against a variety of pathogenic molds. I

The findings herein disclosed are considered remarkable in that in some notable instances compounds that are closely related from the point of view of chemical architecture exhibit quite opposite effects against the same organisms. For example, one compound may exhibit properties as a growth inhibitor against one particular organism while a closely related counterpart may serve to promote increased growth for the same organism. Some of these new compounds exhibit broad antimycotic spectrum,-whereas others exhibit selective antimycotic spectrum.

The compounds which are the subject of this invention are represented by formulas I and II in which the following equation:

0 ER 9. PI H+ RCNH(CH NHCR' HCHO --9 (CH CH2 where n is 2 or 3. The reaction is unexpected since when n is l or a number greater than 3 no reaction occurs and the diamide may be recovered quantitatively from the reaction mixture by removal of volatile materials.

The bioactivity of these various new nitrogencontaining compounds has been established by us in vitro but, as will be apparent to those skilled in the arts pertaining to the growth inhibition of bacteria, yeast, and molds, the compounds, besides being used as such, will for utilitarian purposes commonly be formulated using a diluent that can be either liquid, viscous, or solid.

A wide variety of extending agents is operable, the only significant requirement being that the diluent or extender be inert with respect to the compound involved. Petroleum jellies, various alcohols and polyols, vegetable oils and the like are suitable.

Dehydrated mycological agar at pH 7.0 was used to test the inhibition of the test organisms by the compounds being screened. Suspensions of the test organisms were prepared by transferring a loop of spores into sterile saline. Hardened agar plates were inoculated by placing 3 drops of the suspension onto the agar. The micro-organisms were spread over the surface of the plates with sterile glass rods. These plates were employed in the activity estimation against microbial growth. Filter paper discs 6.5 mm in diameter, made from Whatman Number 1 filter paper were used to evaluate the liquid compounds. Stainless steel cylinders 5 mm ID. were used for the samples which were solids. The paper discs wetted until they are completely saturated with the test compound or stainless steel cylinders containing the test solid compound were placed on the surface of the agar plates inoculated with the test organisms. To eliminate any errors which could result from an insufficient number of tests, a miniumum of three experiments, at different times, employing duplicate plates were made for each compound under test. All plates were incubated at the optimum growing temperature for each organisms and readings were taken after 24, 48, 72, and hr periods.

The organisms used in the tests were Trichoplzyton rubrum, T. violaceum, Microsporum gypseum, and Aspergillus flavus. They were obtained from stock cultures. The data from these tests are tabulated in Table I. The physical constants and analytical data for the 1,3-diacyl derivatives of imidazolidine and hexahydropyrimidine used in the tests are tabulated in Table 11.

Specific examples showing the preparation of each of the new compounds being claimed are set forth below along with appropriate data in tabular form which is being submitted for the purpose of establishing the growth inhibiting properties of the claimed compounds.

EXAMPLE 1 l,3-Diacetylimidazolidine Four grams (0.028 mole) of N,N-

ethylenebisacetamide, 4.4 grams (0.053 mole) of a 36.8 percent formaldehyde solution, ml. of acetic acid, and 0.3 ml of concentrated hydrochloric acid were placed in a flask equipped with stirring bar. The temperature was raised to 50C with stirring, after which the reaction was continued for 2 hours. The acetic acid, excess formalin and hydrochloric acid were removed by distillation of reduced pressures. The residue was given two recrystallizations from absolute ethyl alcohol and then dried over phosphorus pentoxide in a vacuum disiccator. The product, l,3- diacetylimidazolidine, was obtained in 80 percent yield.

EXAMPLE 2 l,3-Dibutyrylimidazolidine This compound was prepared by the procedure of Example 1 from 3 grams (0.015 mole) of N,N'- ethylenebisbutyramide, 2.7 grams (0.032 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic acid and 0.3 ml of concentrated hydrochloric acid. The product. 1,3-dibutyrylimidazolidine was obtained in 78 percent yield. 3

EXAMPLE 3 1,3-Dipentaneylimidazolidine This compound was prepared by the procedure of Example 1 from 4 grams (0.018 mole) of N,N'- ethylenebispentanamide, 3.2 grams (0.039 mole) of a 36.8 percent formaldehyde solution, and 0.3 ml of concentrated hydrochloric acid. The product, l,3- dipentanoylimidazolidine, was obtained in 90 percent yield.

EXAMPLE 4 l,3-Dihexanoylimidazolidine Three grams (0.012 mole) of N,N'-

EXAMPLE 5 1,3-Diheptanoylimidazolidine This compound was prepared by the procedure of Example 4 from 4 grams (0.014 mole) of N,N'- ethylenebisheptanamide, 1.5 grams (0.018 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic acid and 0.3 ml of concentrated hydrochloric acid. The product, 1,3-diheptanoylimidazolidine was obtained in percent yield.

EXAMPLE 6 l,3-Dioctanoylimidazolidine This compound was prepared by the procedure of Example 4 from 4 grams (0.013 mole) of N,N'- ethylenebisoctanamide, 2.3 grams (0.028 mole) of a 36.8 percentformaldehyde solution, 25 ml of acetic acid, and 0.3 ml of concentrated hydrochloric acid. The product, l,3-dioctanoylimidazolidine, was obtained in 90 percent yield.

EXAMPLE 7 l,3-Dinonanoylimidazolidine This compound was prepared by the procedure of Example 4 from 4 grams (0.012 mole) of N,N'- ethylenebisnonanamide, 1.3 grams (0.016 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic acid, and 0.3 ml of concentrated hydrochloric acid. The product, 1,3-dinonanoylimidazolidine, was obtained in 90 percent yield.

EXAMPLE 8 1 ,3-Didecanoy1imidazolidine This compound was prepared by the procedure of Example 4 from 4 grams (0.011 mole) of N,N'- ethylenebisdecanamide, 2 grams (0.025 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic acid and 0.3 ml of concentrated hydrochloric acid. The product, l,3-didecanoylimidazolidine, was obtained in 90 percent yield.

EXAMPLE 9 l,3-Dipalmitoylimidazolidine This compound was prepared by the procedure of Example 4 from 3.2 grams (0.006 mole) of N,N'- ethylenebispalmitamide, 1.1 grams (0.013 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic acid and 0.3 ml of concentrated hydrochloric acid. The product, l,3-dipalmitoylimidazolidine, was obtained in 89 percent yield.

EXAMPLE 10 l,3-Distearoylimidazolidine This compound was prepared by the procedure of Example 4 from 4 grams (0.007 mole) of N,N'- ethylenebisstearamide, 1.2 grams (0.014 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic acid and 0.3 m1 of concentrated hydrochloric acid. The product, 1,3-distearoylimidazolidine, was obtained in 90 percent yield.

EXAMPLE ll l,3-Dioleoylimidazolidine This compound was prepared by the procedure of Example 4 from 3 grams (0.005 mole) of N,N'-

ethylenebisoleamide, 1.1 grams (0.013 mole) ofa 36.8 percent formaldehyde solution, 25 ml of acetic acid and 0.3 ml of concentrated hydrochloric acid. The

product, 1,3-dioleoylimidazolidine, was obtained in 90 percent yield.

EXAMPLE 12 1,3-Diacetylhexahydropyrimidine Four grams (0.025 mole) of= N,N'- propylenebisacetamide, 4.5 grams (0.055 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic acid, and 0.3 ml of concentrated hydrochloric acid were placed in a flask equipped with stirring bar. The temperature was raised to 50C with stirring, after which the reaction was continued for 2 hours. The acetic acid, excess formalin and hydrochloric acid were removed by distillation at reduced pressure. The product, l,3-diacetylhexahydropyrimidine, wasobtained in quantitative yield.

EXAMPLE l3 1,3-Dibutyrylhexahydropyrimidine This compound was prepared by the procedure of Example 12 from 4 grams (0.019 mole) of N,N- propylenebisbutyramide, 3.4 grams (0.042 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic -acid, and 0.3 ml of concentrated hydrochloric acid.

The product, 1,3-dibutyrylhexahydropyrimidine, was obtained in quantitative yield.

EXAMPLE 14 1 ,3-Dipentanoylhexahydropyrimidine Four grams (0.017 mole) of N,N

EXAMPLE 15 1,3-Dihexanoylhexahydropyrimidine Three grams (0.01 1 mole) of N,N

propylenebishexanamide, 1.5 grams (0.018 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic acid and 0.3 ml ofconcentrated hydrochloric acid were placed in a flask equipped with stirring bar. The temperature was raised to 50C and the reaction was continued for 2 hours. The mixture was cooled, diluted with cold water, extracted with benzene, washed with water and dried over anhydrous sodium sulfate. After filtration, the solvent was removed by stripping under reduced pressure,'leaving the product, l,3-dihexanoylhexahydropyrimidine, in 94 percent yield.

EXAMPLE 16 1,3-Diheptanoylhexahydropyrimidine This compound was prepared by the procedure of Example 15 from 4 grams (0.013 mole) of N,N-

propylenebisheptanamide, 2.4 grams (0.029 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic acid and 0.3 m1 of concentrated hydrochloric acid. The

product, l,3-diheptanoylhexahydropyrimidine, was obtained in 84 percent yield.

EXAMPLE 17 1,3-Dioctanoylhexahydropyrimidine This compound was prepared by the procedure of Example 15 from 4 grams (0.012 mole) of N,N- propylenebisoctanamide, 2.6 grams (0.031 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic acid and 0.3 ml of concentrated hydrochloric acid. The product, 1,3-dioctanoylhexahydropyrimidine, was obtained in percent yield.

EXAMPLE 18 1,3-Dinonanoylhexahydropyrimidine This compound was prepared by the procedure of Example 15 from 4 grams (0.011 mole) of N,N- propylenebisnonanamide, 2 grams (0.024 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic acid and 0.3 ml of concentrated hydrochloric acid. The product, 1,3-dinonanoylhexahydropyrimidine, was obtained in 92 percent yield.

EXAMPLE l9 1,3-Didecanoylhexahydropyrimidine This compound was prepared by the procedure of Example 15 from 4 grams (0.011 mole) of N,N- propylenebisdecanamide, 2 grams (0.024 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic acid and 0.3 ml of concentrated hydrochloric acid. The product, 1,3-didecanoylhexahydropyrimidine, was obtained in 90 percent yield.

EXAMPLE 20 1,3-Dipalmitoylhexahydropyrimidine Three grams (0.005 mole) of N,N

propylenebispalmitamide, 1.5 grams (0.018 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic acid and 0.3 ml of concentrated hydrochloric acid were placed in a flask equipped with stirring bar. The temperature was raised to 50C with stirring after which the reaction was continued for 2 hours. After the addition of cold water, the white precipitate that formed was removed by filtration employing a Buchner funnel, washed with water, recrystallized from methyl alcohol and dried in a vacuum desiccator over phosphorous pentoxide. The product, l,3-dipalmitoylhexahydropyrimidine, was obtained in 90 percent yield.

EXAMPLE 21 1,3-Distearoylhexahydropyrimidine This compound was prepared by the procedure of Example 20 from 3 grams (0.05 mole) of N,N- propylenebisstearamide, 1 grams (0.012 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic acid and 0.3 ml concentrated hydrochloric acid. The product, 1,3-distearoylhexahydropyrimidine, was obtained in 90 percent yield.

EXAMPLE 22 1,3-Dio1eoylhexahydropyrimidine This compound was prepared by the procedure of Example 15 from 4 grams (0.007 mole) of N,N- propylenebisoleamide, 1.2 grams (0.015 mole) of a 36.8 percent formaldehyde solution, 25 ml of acetic acid and 0.3 ml of concentrated hydrochloric acid. The product, l,3-dioleoylhexahydropyrimidine, was obtained in 88 percent yield.

EXAMPLE 23 N-(9,10-epithiooctodecanoyl)morpholine 139 g (0.37 mole) of N-(9.10-epoxystearoyl)morpholine was added dropwise at room temperature to a well stirred solution suspension containing 74 g (0.97

10 3.68 percent, S 7.80 percent.

TABLE 1 Antimycotic Activity of 1,3-Diacyl Derivatives of lmidazolidine and Hexahydropyrimidine Sample Antimicrobial Activity No. Compound Micro-organism A B C D E F G l 1.3-Diacetylimidazolidine 2 1.3-Dihutyrylimidazolidine X -11- X 3 1.3-Di entanoylimidazolidine 4 l.3-Dihexanoylimidazolidine +1- -ll- -l1- 5 1.3-Diheptanoylimidazolidine XX X 6 1,3-Dioctanoylimidazolidine 7 l.3-Dinonanoylimidazo1idinc +1 X X 8 1.3-Didecanoylimidazolidine XX X X X 9 1.3-Dipalmitoylimidazolidine XX 10 1,3-Distearoylimidazolidine X X X XX 1 l 1.3-Diolcoyltmidazolidine XX X XX 12 1.3-Diacetylhexahydropyrimidine -H- l3 1,3-Dihutyrylhcxahydro yrimidine -l1- 14 1.3-Dipentanoy1hexahydiopyrimidine -l-l- -ll- +1- +1- 15 1.3-Dihexanoylhexahydropyrimidine +1- -ll- +1- 16 1.3-Dihcptano?/lhexahydropyrimidine -+-l- +1- ll- 17 l .3-Dioctanoy hexahydropyrimidinc +1- -ll- -11- 1 8 1 ,3-Dinonanoylhexahydropyrimidine XX X XX 19 1 ,3-Didecanoylhexahydropyrimidine XX X X X 20 1.3-Dipalmitoylhcxahydropyrimidine X X X XX 21 1.3-Distearoylhexahydropyrimidine 22 l,3-Dioleoylhexahydropyrimidine 23 ll 1-(9.1O-Epithiooctodecanoyl)morpho- X -ll- XX The zone of inhibition was at least 0.5 cm beyond disc or cylinder area at 120 hrs. The zone of inhibition was less than 0.5 cm beyond disc or cylinder area at 120 hrs. XX Organism failed to grow on disc or cylinder area at 120 hrs. X Slight growth on the saturated disc or cylinder area at 120 hrs. No inhibition detectable A Trit'ltuplrvlon rulrrum. B Micrnxpurum g' \/).\'4'!llll. C .-l.rper qillu.\' fldllIA. D Trir/mplrvmn t'iulm'r'um. E mulirlu u/hiruns. F Bacillus .Yfll't'ilA'. G PAUIHIUHHIIIHA' A'fllt'il'A'.

TABLE 1 l Elemental Analyses and Properties of 1,3-Diacyl Derivatives of lmidazolidine and Hexahydropyrimidine Yield Density N f mp C 7: C 7: H N

% C Exp. Theory Exp. Theory Exp Theory 1,3-Diacetylimidazolidine -92 53.73 53.83 7.77 7.75 17.91 17.94 1.3-Dibutyrylimdazolidine 78 84-86 62.35 62.23 9.77 9.50 13.10 13.20 1,3-Difientanoylimidazolidine 90 89-91 65.61 64.95 10.13 10.06 1 1.75 l 1.66 1.3-Di exanoylimidazolidine 90 91-93 67.25 67.13 10.54 10.52 10.47 10.44 1.3-Diheptano limidazolidine 90 92-94 69.33 68.87 10.97 10.88 9.38 9.45 1.3-Dioctanoy imidazolidine 90 93-95 70.14 70.31 1 1.25 1 1.18 8.63 8.63 l.3-Dinonanoylimidazolidine 90 97-99 71.92 71.55 1 1.55 1 1.44 7.73 7.94 1.3-Didecanovlimidazo1idine 90 100-102 72.52 72.59 1 1.67 1 1.65 7.25 7.36 1.3-Dip toylimidaz01idine 89 108-1 10 76.85 76.30 12.50 12.44 5.04 5.09 ll3-Distearoylimidazoliditie 90 108-110 77.85 77.41 12.79 12.66 4.75 4.63 1,3-Dio1eoy1imidazolidine 90 50-52 77.43 77.87 12.01 12.41 4.66 4.66 1,3-Diacetylhexahydropyrimidine 2 1.1378 1.4911 56.21 56.48 8.44 8.35 16.44 16.47 1,3-Dibutyrylhexahydropyrimidine 1 1.0454 1.4847 63.66 63.71 9.93 9.80 12.47 12.38 1,3-Dipentanoylhexahydropyrimidine 90 1.0244 1.4814 65.50 66.11 10.31 10.31 10.81 11.02 1,3-Dihexanoylhexahydropyrirnidine 94 0.9779 1.4797 67.92 68.06 10.77 10.71 9.96 9.92 1,3-Diheptanoylhexahydropynmtdtne 84 0.9843 1.4768 68.88 69.64 10.96 11.04 8.97 9.02 1,3-Dioctanoylhexahydropyrimidine 90 0.9673 1.4774 70.59 70.96 1 1.35 1 1.32 8.34 8.28 1,3-Dinonanoylhexahydropyrimidine 92 0.9576 1.4760 71.57 72.08 11.33 11.55 7.72 7.64 1,3-Didecanoylhexahydropyrimidine 90 28-30 73,27 73,05 1 1,91 11,75 7,14 7,10 1 ,3-Dipa1mitoylhexahydropyrimidine 90 64-66 76,65 76,31 12, 58 12,54 4,90 4,93 1,3-Distearoylhexahydropyrimidine 90 66-68 73,05 77,73 13,3 12,72 4,37 4,53 1,3-Dioleoylhexahydropyrimidine 88 0.9183. 77,75 77,93 11,95 12,44 4,54 4.55

, Uncorrected.

The yield was quantitative.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECT-ION PATENTNO. 3,875,159

DATED April 1, 1975 INVENTOR(S) I Robert R. Mod, Frank C. Magne, Gene Sumrell, Arthur F.

. Novak and James M Solar 7 It IS certrfred that error appears tn the above-Identified patent and that sald Letters Patent are hereby corrected as shown below: j

The following statement should appear in the heading in column 1:

Assignee: The United States of America, as

represented by the Secretary of Agriculture Signed and Scaled this twenty-fifth Of November 19 75 [SEAL] Attest:

RUTH C. MASON l C. MARSHALL DANN Arresting Officer Commissioner of Patents and Trademarks 

1. 1,3-DIACETYLHEXAHYDROPYRIMIDINE.
 2. 1,3-Dibutyrylhexahydropyrimidine.
 3. 1,3-Dipentanoylhexahydropyrimidine.
 4. 1,3-Dihexanoylhexahydropyrimidine.
 5. 1,3-Diheptanoylhexahydropyrimidine.
 6. 1,3-Dioctanoylhexahydropyrimidine.
 7. 1,3-Dinonanoylhexahydropyrimidine.
 8. 1,3-Didecanoylhexahydropyrimidine.
 9. 1,3-Dipalmitoylhexahydropyrimidine.
 10. 1,3-Distearoylhexahydropyrimidine.
 11. 1,3-Dioleoylhexahydropyrimidine. 